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The BMN 165 clinical development program has been designed to demonstrate the safety and efficacy of BMN 165 in reducing blood Phe concentrations in patients 18 to 70 years old with hyperphenylalaninemia due to PKU. Study BMN 165-301 is a Phase 3, open-label, randomized study designed to further characterize the safety of BMN 165 during two induction, titration, and maintenance dose regimens in adults with PKU who have not had previous exposure to BMN 165 (naive). Subjects will be randomized (1:1) to titrate up to one of two dose regimens. Other key features of this study are the dose regimens chosen for induction and titration; the study duration; self administration of study drug; and the chosen tertiary objectives.

All subjects receive Study Drug. Subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day.Eligible subjects will be randomized 1:1 using an IWRS to titrate to one of two dose regimens:

20 mg/day or 40 mg/day. The randomization will be stratified by blood Phe levels of 600 to 900 µmol/L and >900 µmol/ using the last available blood Phe concentration prior to Day 1 of the study.

Primary Purpose:

Treatment

Official Title:

A Phase 3, Open-Label, Randomized, Multi-Center Study to Assess the Safety & Tolerability of an Induction, Titration, and Maintenance Dose Regimen of BMN 165 Self Administered by Adults With PKU Not Previously Treated With BMN 165

Subjects who meet the eligibility criteria will be randomized 1:1 to titrate to one of two dose regimens: 20 mg/day or 40 mg/day. The randomization will be stratified by the last available blood Phe concentration prior to Day 1 (600 to 900 μmol/L and > 900 μmol/L).

Drug: BMN 165

After informed consent, eligible subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day. All subjects will initiate IP at a fixed-dose of 2.5 mg/week for 4 weeks (Induction).

After the Induction Period, subjects will enter the Titration Period (Week 5 up to Week 32) where they will increase their weekly BMN 165 dose to a daily dose regimen of 20 mg/day or 40 mg/day. The Titration Period will be individualized to each subject based on a minimum of 6 weeks (the time it takes to reach a dose regimen of 20 mg/day with no dose interruptions) and up to 28 weeks (accounts for dose interruptions due to AEs). Subjects will stop titration once they have achieved either the 20 mg/day or 40 mg/day dose. A maintenance dose will be administered for 4 weeks.

Other Names:

rAvPAL-PEG

Pegvaliase

Active Comparator: BMN 165, 40mg/day

Subjects who meet the eligibility criteria will be randomized 1:1 to titrate to one of two dose regimens: 20 mg/day or 40 mg/day. The randomization will be stratified by the last available blood Phe concentration prior to Day 1 (600 to 900 μmol/L and > 900 μmol/L).

Drug: BMN 165

After informed consent, eligible subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day. All subjects will initiate IP at a fixed-dose of 2.5 mg/week for 4 weeks (Induction).

After the Induction Period, subjects will enter the Titration Period (Week 5 up to Week 32) where they will increase their weekly BMN 165 dose to a daily dose regimen of 20 mg/day or 40 mg/day. The Titration Period will be individualized to each subject based on a minimum of 6 weeks (the time it takes to reach a dose regimen of 20 mg/day with no dose interruptions) and up to 28 weeks (accounts for dose interruptions due to AEs). Subjects will stop titration once they have achieved either the 20 mg/day or 40 mg/day dose. A maintenance dose will be administered for 4 weeks.

Assessments and procedures for safety and blood Phe concentration will be performed every 4 weeks throughout this study. Safety will be monitored throughout the study by assessment of vital signs, physical examination, electrocardiograms (ECGs), AEs, concomitant medications, and clinical laboratory tests (chemistry, hematology, and urinalysis).

Secondary Outcome Measures
:

blood phe concentration [ Time Frame: 1 to 36 weeks ]

Subjects will be assessed for plasma blood Phe concentration at baseline (predose on Day 1), Week 3, Week 4, and every 4 weeks thereafter.

Other Outcome Measures:

Metabolism [ Time Frame: 1 to 36 weeks ]

All patients will complete a 3-day diety diary to be submitted baseline (predose on Day 1), Week 4, and every 4 weeks thereafter. Their dietary intake will be calculated and analyzed through a computer software program, "Metabolic Pro" The diary data will be analyzed by nutritional software for total kcals, protein, phe, tyrosine, and the percentage of DRI provided for protein, phe, tyrosine, vitamins, and minerals will be evaluated on a monthly basis.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

18 Years to 70 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA

Individuals eligible to participate in this study must meet all of the following criteria:

A current diagnosis of PKU with the following:

Current blood Phe concentration >600 µmol/L at screening and

Average blood Phe concentration of >600 µmol/L over the past 6 months (per available data)

Have no previous exposure to BMN 165

Are ≥18 and ≤70 years of age at the time of screening

Subjects who are < 18 years of age but are already enrolled into the study may continue to participate

If taking Kuvan, have a treatment end date ≥14 days prior to Day 1 (ie, first dose of BMN 165)

Are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures

Are willing and able to comply with all study procedures

Has identified a person who is ≥ 18 years of age who has the neurocognitive and linguistic capacities to comprehend and complete the POMS-Observer-rated scale

Has identified a competent person or persons who are ≥ 18 years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration until dose titration has completed and if needed upon return to dosing after an AE and per investigator determination.

A home healthcare nurse may perform the study drug observations.

For females of childbearing potential, must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. (Females are considered not of childbearing potential if they have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy.)

If sexually active, must be willing to use 2 acceptable methods of contraception while participating in the study and 4 weeks after the study.

Males post vasectomy 2 years with no known pregnancies for at least 2 years do not need to use any other forms of birth control during the study.

Females who have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy do not need to use any other forms of contraception during the study.

Have received documented approval from a study dietician confirming that the subject is capable of maintaining their diet in accordance with dietary information presented in the protocol.

Have neurocognitive and linguistic capacities to comprehend and answer investigator's prompts for the ADHD RS- Investigator rated instrument and to complete the POMS-Subject rated scale.

If applicable, maintained stable dose of medication for attention deficit hyperactivity disorder (ADHD), depression, anxiety, or other psychiatric disorder for ≥8 weeks prior to enrollment and willing to maintain stable dose throughout study unless a change is medically indicated.

Are in generally good health, as evidenced by physical examination, clinical laboratory evaluations and ECG tests performed at screening

EXCLUSION CRITERIA

Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:

Use of any investigational product or investigational medical device within 30 days prior to screening or requirement for any investigational agent prior to completion of all scheduled study assessments.

Use of any medication that is intended to treat PKU (except Kuvan), including the use of large neutral amino acids, within 2 days prior to administration of study drug Day 1 (first dose of BMN 165). Note: Kuvan treatment must be stopped ≥14 days before Day 1

Use or planned use of any injectable drugs containing PEG (other than BMN 165), including medroxyprogesterone injection, within 3 months prior to screening and during study participation